CIED Related Infection
Conditions
Brief summary
Medtronic , Inc. is sponsoring the World-wide Randomized Antibiotic Envelope Infection Prevention Trial (WRAP-IT), a randomized, prospective, multi-center, single blinded, post-market, interventional clinical study. This study will evaluate the ability of the TYRX™ envelope to reduce major Cardiac Implantable Electronic Device (CIED) infections through 12-months post-procedure following CIED generator replacement, upgrade, revision, or de novo cardiac resynchronization therapy defibrillator (CRT-D) implant. Additionally, this large device study provides the unique opportunity to prospectively characterize the performance of Medtronic's lead monitoring features in subjects whose CIED system includes a transvenous right ventricular (RV) defibrillation lead. Finally, the WRAP-IT study will serve as a post-approval study for those geographies requiring a post-approval study of the TYRX™ envelope.
Interventions
DEVICETYRX™ Absorbable Antibacterial Envelope
Sponsors
The Cleveland Clinic
Medtronic Cardiac Rhythm and Heart Failure
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Patient is willing to sign and date the study patient informed consent (PIC) form * Patient is at least 18 years of age and meets age requirements per local law * Patient is planned to undergo at least one of the following: a. Patient has existing cardiac implantable electronic device (CIED) and is undergoing implantable pulse generator (IPG) (including cardiac resynchronization therapy pacemaker \[CRT-P\]), implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy defibrillator (CRT-D) replacement or upgrade with a new Medtronic generator i. Subjects planned to have leads added, or extracted and added for upgrades can be enrolled OR b. Patient will undergo a de novo Medtronic CRT-D system implant per approved indications OR c. Patient has existing study eligible Medtronic CIED in which the pocket was not accessed within the last 365 days, and is undergoing pocket or lead revision * Willing to provide the contact information for the physician who provides followup for his/her CIED * Willing and able to comply with scheduled follow-up and study related activities
Exclusion criteria
* Known allergy to minocycline or rifampin or their derivatives, or any other known contraindications to implantation of the TYRX envelope. * Current therapy with chronic oral immunosuppressive agents or ≥ 20mg/day of Prednisone or equivalent. * Hemodialysis or peritoneal dialysis. * Prior Cardiac transplantation or existing Ventricular Assist Device (VAD). * Require long-term vascular access for any reason. * Prior history of a CIED infection, other prosthetic device infection, or endovascular infection, including endocarditis, in the past 12 months. * Physical, clinical, or laboratory signs or symptoms consistent with an active infection (including but not limited to pneumonia, urinary tract, cellulitis, or bacteremia) * Systemic lupus erythematous, because minocycline has been reported to aggravate this condition * Female patient who is pregnant, or of childbearing potential and not on a reliable form of birth control. Women of childbearing potential are required to have a negative pregnancy test within 7 days prior to device procedure * Participation in another study that may confound the results of this study. Co-enrollment in concurrent trials is only allowed when documented pre-approval is obtained from the Medtronic study manager.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 12 Month Kaplan-Meier Estimate of Major CIED Infection Rate | Implant to 12 months | CIED infections are defined as (1) superficial cellulitis in the region of the CIED pocket with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space (generator pocket) surgical site infection that meets the Centers for Disease Control and Prevention criteria, independent from time of surgery, (3) persistent bacteremia, or (4) endocarditis. Major CIED infections are defined as a CIED infection resulting in one or more of the following: * CIED system removal * Any invasive procedure (e.g. pocket opened) without system removal * Treatment with antibiotic therapy if the subject is not a candidate for system removal and infection recurrence after completion of antibiotic therapy or evidence of deep infection with wound dehiscence, erosion, or purulent drainage * Death |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 12 Month Kaplan-Meier Estimate of Major or Minor CIED Infection | Implant to 12 months | Major CIED infections are defined above. Minor CIED infections are defined as CIED infections that do not meet the definition of a major CIED infection |
| 12 Month Kaplan-Meier Estimate of a CIED Procedure Related or System Related Complication | Implant to 12 months | * A CIED system related event is defined as an adverse event related to the CIED system which includes the device, leads, implant tool(s), programmer, or TYRX envelope (if applicable) * A CIED procedure related event is defined as an adverse event that occurs due to any procedure related to the implantation or surgical modification of the system including the TYRX envelope (if applicable) * A procedure or system related complication is defined as an adverse event related to a CIED procedure or the CIED system that results in at least one of the following: Death,Termination of significant device function, Invasive intervention |
| Kaplan-Meier Estimate of a Major Infection Throughout Follow-up | Throughout study follow-up Kaplan-Meier Estimate is at 36 Months | CIED infections are defined as (1) superficial cellulitis in the region of the CIED pocket with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space (generator pocket) surgical site infection that meets the Centers for Disease Control and Prevention criteria, independent from time of surgery, (3) persistent bacteremia, or (4) endocarditis. Major CIED infections are defined as a CIED infection resulting in one or more of the following: * CIED system removal * Any invasive procedure (e.g. pocket opened) without system removal * Treatment with antibiotic therapy if the subject is not a candidate for system removal and infection recurrence after completion of antibiotic therapy or evidence of deep infection with wound dehiscence, erosion, or purulent drainage * Death |
Countries
Austria, Belgium, Canada, Chile, China, Denmark, Finland, France, Germany, Greece, Israel, Italy, Malaysia, Netherlands, Norway, Poland, Portugal, Saudi Arabia, Singapore, Slovakia, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Pre-assignment details
There were 92 total patients that were enrolled into the study, but not randomized. After enrollment, but prior to randomization, 2 patients died, 31 patients were found to not meet eligibility criteria, 50 patients withdrew, 1 investigator withdrew the patient and 8 patients had an other or unknown reason for not being randomized.
Participants by arm
| Arm | Count |
|---|---|
| TYRX Envelope The Medtronic TYRX Absorbable Antibacterial Envelope is an absorbable sterile prosthesis designed to hold a pacemaker pulse generator or defibrillator to create a stable environment when implanted in the body. The purpose of the absorbable coating is to act as a carrier for the antimicrobial agents.
TYRX Absorbable Antibacterial Envelope | 3,495 |
| Control No TYRX envelope, bare CIED | 3,488 |
| Total | 6,983 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 170 | 188 |
| Overall Study | Had other reason | 26 | 32 |
| Overall Study | Lost to Follow-up | 66 | 69 |
| Overall Study | Physician Decision | 40 | 34 |
| Overall Study | Withdrawal by Subject | 64 | 53 |
Baseline characteristics
| Characteristic | Control | Total | TYRX Envelope |
|---|---|---|---|
| Age, Continuous | 70.1 years STANDARD_DEVIATION 12.4 | 70.1 years STANDARD_DEVIATION 12.5 | 70.0 years STANDARD_DEVIATION 12.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 4 Participants | 12 Participants | 8 Participants |
| Race (NIH/OMB) Asian | 91 Participants | 188 Participants | 97 Participants |
| Race (NIH/OMB) Black or African American | 207 Participants | 409 Participants | 202 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 7 Participants | 16 Participants | 9 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 485 Participants | 961 Participants | 476 Participants |
| Race (NIH/OMB) White | 2691 Participants | 5389 Participants | 2698 Participants |
| Region of Enrollment Austria | 29 participants | 58 participants | 29 participants |
| Region of Enrollment Belgium | 35 participants | 71 participants | 36 participants |
| Region of Enrollment Canada | 131 participants | 262 participants | 131 participants |
| Region of Enrollment Chile | 3 participants | 5 participants | 2 participants |
| Region of Enrollment China | 19 participants | 37 participants | 18 participants |
| Region of Enrollment Denmark | 36 participants | 70 participants | 34 participants |
| Region of Enrollment Finland | 23 participants | 47 participants | 24 participants |
| Region of Enrollment France | 94 participants | 188 participants | 94 participants |
| Region of Enrollment Germany | 11 participants | 23 participants | 12 participants |
| Region of Enrollment Greece | 43 participants | 88 participants | 45 participants |
| Region of Enrollment Israel | 44 participants | 91 participants | 47 participants |
| Region of Enrollment Italy | 86 participants | 174 participants | 88 participants |
| Region of Enrollment Malaysia | 41 participants | 83 participants | 42 participants |
| Region of Enrollment Netherlands | 69 participants | 139 participants | 70 participants |
| Region of Enrollment Norway | 32 participants | 64 participants | 32 participants |
| Region of Enrollment Poland | 16 participants | 34 participants | 18 participants |
| Region of Enrollment Portugal | 17 participants | 37 participants | 20 participants |
| Region of Enrollment Saudi Arabia | 10 participants | 21 participants | 11 participants |
| Region of Enrollment Singapore | 8 participants | 19 participants | 11 participants |
| Region of Enrollment Slovakia | 31 participants | 60 participants | 29 participants |
| Region of Enrollment Spain | 48 participants | 100 participants | 52 participants |
| Region of Enrollment Sweden | 47 participants | 92 participants | 45 participants |
| Region of Enrollment Switzerland | 33 participants | 63 participants | 30 participants |
| Region of Enrollment United Kingdom | 141 participants | 276 participants | 135 participants |
| Region of Enrollment United States | 2441 participants | 4881 participants | 2440 participants |
| Sex: Female, Male Female | 976 Participants | 1973 Participants | 997 Participants |
| Sex: Female, Male Male | 2512 Participants | 5010 Participants | 2498 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 349 / 3,495 | 365 / 3,488 |
| other Total, other adverse events | 286 / 3,495 | 221 / 3,488 |
| serious Total, serious adverse events | 1,553 / 3,495 | 1,548 / 3,488 |
Outcome results
Primary
12 Month Kaplan-Meier Estimate of Major CIED Infection Rate
CIED infections are defined as (1) superficial cellulitis in the region of the CIED pocket with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space (generator pocket) surgical site infection that meets the Centers for Disease Control and Prevention criteria, independent from time of surgery, (3) persistent bacteremia, or (4) endocarditis. Major CIED infections are defined as a CIED infection resulting in one or more of the following: * CIED system removal * Any invasive procedure (e.g. pocket opened) without system removal * Treatment with antibiotic therapy if the subject is not a candidate for system removal and infection recurrence after completion of antibiotic therapy or evidence of deep infection with wound dehiscence, erosion, or purulent drainage * Death
Time frame: Implant to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TYRX Envelope | 12 Month Kaplan-Meier Estimate of Major CIED Infection Rate | 0.7 Percentage of subjects |
| Control | 12 Month Kaplan-Meier Estimate of Major CIED Infection Rate | 1.2 Percentage of subjects |
p-value: 0.040695.12% CI: [0.36, 0.98]Regression, Cox
Secondary
12 Month Kaplan-Meier Estimate of a CIED Procedure Related or System Related Complication
* A CIED system related event is defined as an adverse event related to the CIED system which includes the device, leads, implant tool(s), programmer, or TYRX envelope (if applicable) * A CIED procedure related event is defined as an adverse event that occurs due to any procedure related to the implantation or surgical modification of the system including the TYRX envelope (if applicable) * A procedure or system related complication is defined as an adverse event related to a CIED procedure or the CIED system that results in at least one of the following: Death,Termination of significant device function, Invasive intervention
Time frame: Implant to 12 months
Population: Per the Statistical Analysis Plan, the statistical inference for this objective was based on the As-Treated cohort instead of the Intention-to-Treat cohort. Per the cohort definition, subjects are analyzed based on the treatment (envelope or no envelope) and the device class (low or high power) that was actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TYRX Envelope | 12 Month Kaplan-Meier Estimate of a CIED Procedure Related or System Related Complication | 6.0 Percentage of subjects |
| Control | 12 Month Kaplan-Meier Estimate of a CIED Procedure Related or System Related Complication | 6.9 Percentage of subjects |
p-value: <0.0195.12% CI: [0.77, 1.12]Regression, Cox
Secondary
12 Month Kaplan-Meier Estimate of Major or Minor CIED Infection
Major CIED infections are defined above. Minor CIED infections are defined as CIED infections that do not meet the definition of a major CIED infection
Time frame: Implant to 12 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TYRX Envelope | 12 Month Kaplan-Meier Estimate of Major or Minor CIED Infection | 1.4 Percentage of subjects |
| Control | 12 Month Kaplan-Meier Estimate of Major or Minor CIED Infection | 2.2 Percentage of subjects |
p-value: 0.024895.12% CI: [0.47, 0.96]Regression, Cox
Secondary
Kaplan-Meier Estimate of a Major Infection Throughout Follow-up
CIED infections are defined as (1) superficial cellulitis in the region of the CIED pocket with wound dehiscence, erosion, or purulent drainage, (2) deep incisional or organ/space (generator pocket) surgical site infection that meets the Centers for Disease Control and Prevention criteria, independent from time of surgery, (3) persistent bacteremia, or (4) endocarditis. Major CIED infections are defined as a CIED infection resulting in one or more of the following: * CIED system removal * Any invasive procedure (e.g. pocket opened) without system removal * Treatment with antibiotic therapy if the subject is not a candidate for system removal and infection recurrence after completion of antibiotic therapy or evidence of deep infection with wound dehiscence, erosion, or purulent drainage * Death
Time frame: Throughout study follow-up Kaplan-Meier Estimate is at 36 Months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TYRX Envelope | Kaplan-Meier Estimate of a Major Infection Throughout Follow-up | 1.3 Percentage of subjects |
| Control | Kaplan-Meier Estimate of a Major Infection Throughout Follow-up | 1.9 Percentage of subjects |
p-value: 0.040295.12% CI: [0.4, 0.98]Regression, Cox